- diketo -



Patented Nov. 27, 1951 UNITED STATES PATENT OFFICE 4,6 DIKETO 5,5 DISUBSTITUTED PYRIMI- DINES AND PROCESS FOR PREPARING SAME William R. Boon,Herbert G. Carrington, and Charles Henry Vasey, Blackley, Manchester,England, assignors to Imperial Chemical Industries Limited, acorporation of Great Britain No Drawing. Application July 11, 1950,Serial No. 173,248. In Great Britain July 27, 1949 14 Claims.

i This invention relates to new pyrimidine the derivatives which we havefound to possess anti-convulsant properties.

According to our invention we provide the said new pyrimidinederivatives, namely compounds of the general formula:

r oo-Nn,

o-NH wherein R1 stands for a monocyclic carbocyclic A radical or for analkenyl radical of not more than 3 carbon'atoms, R2v stands for an alkylradical or an. alkenyl-radical of not more than 3 carbon vatoms and-Rsstands for hydrogen or an alkyl radical ofnot more than 4 carbon atoms.

According to a further feature of the inventlon we providea process forthe manufacture of the said new pyrimidine derivatives which comprisesreduction of a compound of the formula wherein X stands foroxygen or forsulphur and whereby Y stands for hydrogen, or, where X stands forsulphur, an alkyl radical.

It will be understood that when Y stands for hydrogen the compounds ofthe aboveiormula may also be written:

ONRx ONH The reduction of the said compounds may. for example be broughtabout by means of hydrogen,

either electrolytically or by means of hydrogen in presence of acatalyst, for example of Raney ,RiRa

nickel.

According to yet a further feature of the invention we provide a processfor the manufacture of the said new pyrimidine derivatives whichcomprises condensation of a malondiamide derivative of the formulaCONHR:

RlRflC CONE:

wherein R1, R2 and Re have the meaning set forth above, with iormamide.

The said condensation may be brought about conveniently by heating thereactants together.

In experimental animals the said new pyrimidine derivatives ShOW 5 ,101!finti-convulsant properties as to render them of potential value in thecontrol of epilepsy. The said anti-convulsant properties are superior tothose shown by the corresponding barbituric acid from which the newpyrimidine derivatives are, or may be regarded as being, derived.

The invention is illustrated but not limited by the following examplesin which the parts are by weight.

Example 1 50 parts of Raney nickel are added to a solution of 10 partsof 5-phenyl-5-ethyl-2-thiobarbituric acid in 250 parts of ethanol andthe mixture is boiled under reflux for one hour. It is then filtered,the residue is extracted with hot ethanol and the extract'is added tothe filtrate. The combined liquid is then evaporated to one tenth of itsvolume and isthen cooled and filtered. The crystalline solid residue is5-phenyl-5- ethylhexahydropyrimidine-4,6-dione of M. P. 281-282 C.

Example 2 50 parts of a -phenylethylmalondiamide and 150 parts offormamide areboiled together under reflux for 2 hours. The mixture isthen cooled to 0 C. and filtered. The solid residue is washed with 50parts of ethanol and then crystalised from 660 parts of an ethanol/watermixture. There is obtained 5-phenyl 5ethylhexahydropyrimidine-4,6-dione, M. P. 281-282 C.

Example 3 Example 4 5 parts 5-phenyl-5-ethylbarbituric acid aresuspended in parts of 80% sulphuric acid in a porous cell. .This cell isthen immersed in 60% aqueous sulphuric acid. A sheet of lead is placedExample 5 16 parts a -phenylmethylmalondiamide (M. P. 150-151 C'.) and55 parts .of :formamide'are boiled together under-reflux during 90minutes. The mixture is then cooledandis filtered. The solid residue iscrystallised from 80% aqueous ethyl alcohol and there is obtained5-phenyl-5- methylhexahydropyrimidine 4,6 dione, "M. P. 295-6 C. 7

There have also been obtained .by processes similar .to that of theabove :example, save that .there is used in place of the ,16 partsbra-phenyl- .a-methylmalondiamide "a corresponding quantity of theappropriately substituted :malondiamide,

5 phenyl-5-n-propylhexahydropyrimidine 4,6-

:dione, P. BOB-:99 5-;phenyl-5-isopropylhexahydropyrimidine-Afidione,TP. 393 C., 5 phenyl-5-allylhexahydropyrimidirre 1- 4,6 .dione, M. P.295-6 C., and 5-cyc1ohexyl-5-n-propylhexahydropyrimidine-4;6-dione, M.P. 326 C.

The appropriately substituted malondiamides used making :theacompoundsmentioned above may be obtained ifrom "the correspondinglysub- ;stituted malonic esters by hydrolysis with aqueous alcoholicsodium hydroxide to give the corresponding malonic acids which areconverted by means of phosphorus pentachloride ,to the malonyl chloridesand these .are finally .reacted with aqueous ammonia. There were thusobtained, for example, .aphenyla-n-wpropylmalondiamide, M. P. 173 C.,a,a-phenylisoprq ylmalondiamide, M. P. 222 C.,a,u.-phenylallylmalondiamide, M. *P. 10'7 -*1-l0 C., and 0.,CL-CYC10-:hexyl-n-nropy1malondiamide, M. ;P 240 241- c.

Err-ample '6 '15 parts of 5-phenyl-5-isopropyl+2thiobarbituric acid, 250parts-of ethyl alcohol and .25 parts *-of freshly prepared Raney nickelare boiled to- P. 301-2 C. and'5-cyclohexyl-5-n-propylhexahydropyrimidine-4,6-dione, M. P. 320 C.

The 5,5-disubstitutede2-thiobarbituric acids used in making thepyrimidine derivatives as 'described above may benbtained .:bycondensation of the appropriatelysubstituted malonic esters withthiourea. There were thus obtained 5- phenyl-5-methyl-2-thiobarbitnricacid, M. P. 210 C., 5-phenyl-5-isopropyl-2-thiobarbituric acid, M. P.186487 C., 5-cyclohexyl-5-ethyl-e2- thiobarbituric acid, M. P. 188-189?C., and ;5-

4 cyclohexyl-B-n-propyl-2-thiobarbituric acid, M. P. 142-144 C.

Example 7 17 parts ,of a,a-phenylethyl=Nethylmalondiamide and parts offormamide areboiled together under reflux for 90 minutes. The mixture isthen cooled, water is added and the mix- ;ture .is thenfiltered. Theresidue is crystallised from water and5-phenyl-1,5-diethylhexahydropyrimidine-4,6-1iione is obtained, M. P. -6C.

By the process of the above example, using in "place of thewphenylethyl-N-ethylmalondiamide, other appropriately substitutedN-alkylmalondiamides, .there have been obtained: 5- phenyl 1,5dimethylhexahydropyrimidine-4,6- dione, M. P. 174- C.,5-phenyl-5-methyl-1-n- "propylhexahydropyrimidine 4,6 dione, M. P. 15.1C., 5-phenyl-5-ethyl-l-methylhexahydropyrimidine-4,6-dione, M. P. -186C., 5- phenyl-fi-ethyl-l-n-propylhexahydropyrimidineeigfi-dione, M. P.124-125 C. and 5-phenyl-5-npropyl-l methylhexahydropyrimidine 4;6 dione,M. P. 166-167 C.

The a,a phenylalkyl N alkylmalondiamides used in the process of theaboveexamples maybe obtained from the appropriately a,a-disubstituted ethylcyanacetates by action firstly of aqueous alcoholic amines to give thea,a-phenylalkyl-N- alkylcyanoacetamides which are then converted to thediamides by means of cold concentrated sulphuric acid. There are thusobtained 11,0.- phenylmethyl N methylmalondiamide, M. P. 153 C.,a,a-phenylmethyl-N n-propylmdlondiamide, M. P. 81 C.,d,a-phenylethyl-N-methylmalondiamide, M. P. 144-145 C., a,a-phenylethyl-N-ethylmalondiamide, M. P. 126-127 C., a,u.-phenylethyl-N-n-propylmalondiamide, M. P. 106- 107 C. anda,aphenyl-n-propyl-N-methylmalondiamide, M. P. 114 -116" C.

Erample 8 1 part of a,a-diall ylmalondiamide is boiled under reflux forone hour with 4 parts of formamide. The mixture is thencooledandfiltered. Thesolid residue is crystallised from aqueous .ethanol and5,5-diallylhexahydropyrimidineAfiedione is obtained, of M. P. 314-5 C.

What weclaim is:

1. New pyrimidine derivatives possessing anticonvulsant properties andhaving the general forula wherein R1 stands for a radical selected fromthe group consisting of monocyclic carbocyclic radicals of six carbonatoms and alkenyl radicals of from 1 to 3 carbon atoms, R2 .stands for aradical selected from the group consisting of alkyl tradicals of from 1to 3 carbonatoms and alkenylradicals of from 1 to "3 carbon atoms and R3stands for a radical selected from the group consisting of hydrogen andalkyl radicals of from 1 to 4 carbon atoms.

2. 5 phenyl -5 ethylhexahydropyrimidine-4,6- dione.

3. Process for the manufacture of newpyrimidine derivatives having thegeneral formula wherein R1 stands for a radical selected from the groupconsisting of monocyclic carbocyclic radicals of six carbon atoms andalkenyl radicals of from 1 to 3 carbon atoms, R2 stands tor a radicalselected from the group consisting of alkyl radicals of from 1 to 3carbon atoms and alkenyl radicals of from 1 to 3 carbon atoms and R3stands for a radical selected from the group consisting of hydrogen andalkyl radicals of from 1 to 4 carbon atoms, which comprises reduction ofa compound of the formula (JO-NR:

wherein R1, R2 and R3 have the meaning stated above, X stands for aradical selected from the group consisting of oxygen and sulphur and Ystands for a radical selected from the group consisting of hydrogen andalkyl radicals.

4. The process of claim 3 wherein the reduction is brought about bymeans of hydrogen.

5. The process of claim 3 wherein the reduction is brought aboutelectrolytically.

6. The process of claim 3 wherein the reduction is brought about bymeans of hydrogen in the presence of a. catalyst.

7. The process or claim 3 wherein the reduction is brought about bymeans of Raney nickel.

8. Process for the manufacture of 5-pheny1-5-ethylhexahydropyrimidine-4,6-dione which comprises reduction of5-phenyl-5-ethylbarbituric acid. a

9. Process for the manufacture of 5-phenyl-5-ethylhexahydropyrimidine-4,6-dione which comprises reduction of5phenyl-5-ethyl-2-thiobarbituric acid.

10. Process for the manufacture of 5-phenyl-5-ethylhexahydropyrimidine-4,6-dione which comprises reduction or a2-alkylthio-5-phenyl-5- ethyltetrahydropyrimldine-4,6-clione.

11. 5 phenyl 1,5 diethylhexahydropyrimidine-4,6-dione.

12. 5 phenyl 5 methylhexahydropyrimidine-4,6-dione.

13. 5 phenyl 5 ethyl 1 n-propylhexa- 2o hydropyriii1idine-4,6-dione.

No references cited.

1. NEW PYRIMIDINE DERIVATIVES POSSESSING ANTICONVULSANT PROPERTIES ANDHAVING THE GENERAL FORULA
 3. PROCESS FOR THE MANUFACTURE OF NEWSPYRIMIDINE DERIVATIVES HAVING THE GENERAL FORMULA